Agomelatine

• Approved Indications:
• Treatment of Major Depressive Disorder (MDD) in adults.
• Off-label or Clinically Accepted Uses:
• Anxiety disorders associated with depression.
• Sleep disturbances related to depression.

• Adults:
• Starting dose: 25 mg orally once daily at bedtime.
• If insufficient clinical response after 2 weeks and drug is well tolerated, dose may be increased to 50 mg once daily at bedtime.
• Maximum recommended dose: 50 mg daily.
• Duration of treatment varies, generally several weeks to months depending on response.
• Pediatrics:
• Safety and efficacy not established; use is not recommended.
• Elderly:
• No specific dose adjustment; use with caution.
• Renal Impairment:
• No dose adjustment needed for mild to moderate impairment; limited data in severe impairment.
• Hepatic Impairment:
• Contraindicated in patients with hepatic impairment or active liver disease.
• Route of Administration:
• Oral, preferably taken at bedtime with or without food.

Agomelatine acts as an agonist at melatonin receptors MT1 and MT2, which helps regulate circadian rhythms and improve sleep patterns disrupted in depression. Additionally, it functions as an antagonist at serotonin 5-HT2C receptors, leading to increased release of norepinephrine and dopamine in the frontal cortex. This dual action contributes to its antidepressant effects by improving mood and normalizing circadian rhythms without typical SSRI side effects like sexual dysfunction.

• Absorption: Rapid, with peak plasma concentration reached within 1-2 hours post-dose.
• Bioavailability: Approximately 5-10% due to extensive first-pass metabolism.
• Distribution: High plasma protein binding (~95%).
• Metabolism: Primarily metabolized by hepatic cytochrome P450 enzymes CYP1A2 and CYP2C9.
• Elimination: Mainly excreted as metabolites via urine (about 80%) and feces (about 20%).
• Half-life: Approximately 1-2 hours.

• Pregnancy: There are no adequate and well-controlled studies in pregnant women. Animal studies have not shown teratogenicity at therapeutic doses. Use only if the potential benefit justifies the potential risk to the fetus.
• Lactation: It is unknown whether agomelatine is excreted in human milk. Caution is advised; breastfeeding is generally not recommended during treatment.

• Antidepressant
• Melatonergic receptor agonist and serotonin 5-HT2C receptor antagonist

• Known hypersensitivity to agomelatine or any component of the formulation.
• Severe hepatic impairment or active liver disease.
• Concomitant use of potent CYP1A2 inhibitors (e.g., fluvoxamine).
• Pregnancy and breastfeeding unless benefits outweigh risks.

• Risk of hepatotoxicity: monitor liver function tests before treatment and periodically during therapy (e.g., at weeks 6, 12, and 24).
• Avoid use if liver enzymes exceed three times the upper limit of normal.
• Monitor for worsening depression and suicidal ideation, especially during initiation or dose changes.
• Use with caution in patients with bipolar disorder due to possible manic switch.
• Caution advised in renal impairment.

• Common Adverse Effects:
• Headache
• Dizziness
• Nausea
• Fatigue
• Somnolence
• Serious/Rare Adverse Effects:
• Elevated liver enzymes (hepatotoxicity)
• Allergic reactions including rash and pruritus
• Suicidal thoughts or behavior

• Strong CYP1A2 inhibitors significantly increase agomelatine plasma concentrations and are contraindicated.
• Moderate CYP2C9 inhibitors may increase levels; caution advised.
• Smoking induces CYP1A2 and may reduce agomelatine efficacy.
• No significant interactions with food; avoid alcohol due to additive CNS effects.

• Recognized by European and other psychiatric guidelines as an effective antidepressant with favorable tolerability and unique chronobiotic properties.
• Emphasis on regular liver monitoring due to risk of hepatotoxicity.
• No major changes in dosing recommendations; research ongoing into additional uses such as anxiety disorders.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep container tightly closed.
• No refrigeration required.